Nebivolol hydrochloride, with the chemical name of (+/−)-di[2-(6-fluoro-dihydrobenzopyran-2-yl)-2-hydroxyethyl]amine (Formula I) hydrochloride, is a highly selective third-generation β-receptor blocker developed by Johnson & Johnson that also has vasodilation effect. It is primarily used for the treatment of mild to moderate hypertension, angina pectoris and congestive heart failure. The Nebivolol hydrochloride clinically used is a mixture of equal amounts of the dextroisomer (Formula Ia) and the levoisomer (Formula Ib), i.e., its racemate (Formula I). The effect of Nebivolol hydrochloride as blocker on β-receptor is mainly derived from the dextroisomer, but other effects depend on the presence of both the dextroisomer and the levoisomer.
The relative configuration of Nebivolol is as follows:

wherein I (S*R*R*R*) represents racemate, which is a racemic mixture consisting of equimolar amounts of D-Nebivolol Ia (SRRR) and its enantiomer L-Nebivolol Ib (RSSS) as shown below.

Both of the levoisomer and the dextroisomer of Nebivolol have important biological activity, the levoisomer has endothelial cell-dependent vasodilation effect, and the dextroisomer has a strong β1-receptor blockade effect. A mixture of the levoisomer and dextroisomer is clinically used now, which allows the activities of the two isomers to be synergistic, ensuring that Nebivolol has a unique advantage in addition to the above β-receptor blockade effect: β1-receptor is selectively antagonized by enhancing release of NO, resulting in vasodilation. It does not affect β2 receptor, and does not cause contraction of bronchial smooth muscle and vascular smooth muscle. Therefore, in view of the important pharmacological value of Nebivolol, it is of great economic and social benefits to develop a process for the preparation of Nebivolol and its optical isomers, which is highly efficient, low-cost, and meets the requirements of industrialization.
The molecular structure of Nebivolol contains four chiral carbon atoms as marked below, wherein isomer S*R*R*R* is the Nebivolol used clinically, and it is represented as racemic mixture containing equimolar amounts of D-isomer with absolute configuration SRRR and its enantiomer L-isomer with absolute configuration RSSS.

Nebivolol is structurally characterized in having certain symmetry. Each of the left and right parts of the molecule has a structural unit of (6-fluoro-benzopyranyl)ethane-2-ol with different configurations. In the left part (part A), the hydroxyl group and the oxygen in the pyran ring is in cis-form, and in the right part (part B), they are in trans-form, and the units in the two parts are linked by a nitrogen atom.
In the prior art literatures, synthesis of Nebivolol is mainly based on the symmetry of its molecule, the parts A and B are synthesized respectively, and then coupled with benzylamine. After separation, purification and deprotection, Nebivolol is achieved.
Specifically, the existing methods for preparation of Nebivolol mainly include the following:
(1) Using the racemic intermediates as raw materials, the fragments in the left and right parts with the relative configurations in Nebivolol molecule are constructed respectively, and then subjected to cross-coupling reaction to prepare the desired product;
The key point of this method is how to prepare the two fragments A and B with high diastereomeric purity in the desired configuration, otherwise the mixture containing the above ten isomers will be obtained after coupling reaction.

The intermediate compounds obtained by coupling two fragments A and B with the desired configurations contain two pairs of diastereoisomers and need to be isolated by recrystallization to give the intermediates with the desired configuration:

Janssen's patent EP 145067 discloses the following synthetic process, characterized in that the chroman aldehyde and trimethylsulfoxonium iodide are reacted in the presence of sodium hydride to give a pair of unequal amounts of diastereoisomers, i.e., the epoxide intermediates MA (S*R*) and MB (R*R*). Epoxide intermediates MA (S*R*) and MB (R*R*) can be separated by chromatography and then be the key intermediates for synthesis of Nebivolol, followed by cross-coupling reaction with benzylamine to give a mixture of SRRR/RSSS and SRSS/RSRR as follows:

which is then separated by repeated fractional crystallizations, and deprotected by hydrogenolysis to obtain S*R*R*R*-Nebivolol, as follows:

Although the above-mentioned preparation method is widely used in the industry now, the main problem of this method is that the key intermediates need to be separated by column chromatography, thus it is of high cost to use in large-scale production. In addition, the reaction conditions for preparing the epoxides from unstable chroman aldehyde are harsh, the yield is low and the reagents used are expensive.
(2) Cyanide Derivative Method of the Patent WO2007/009143 (CN101243062)
The method is carried out by reaction of racemic chroman aldehyde with sodium bisulfite and sodium cyanide to give nitrile alcohol intermediates, which are then separated by column chromatography to yield a pair of cis- and trans-nitrile alcohol diastereomers.

The cis-nitrile alcohol intermediate is acetylated and then subjected to catalytic hydrogenation to convert to the corresponding aldehyde, which is then hydrolyzed to give the corresponding aldol intermediate.
The trans-nitrile alcohol intermediate is then catalytically hydrogenated to the corresponding alcohol amine, which is reacted with benzoyl chloride to give the amide, followed by reduction to give the benzylamine intermediate, which is finally condensed with the aldol intermediate to give a pair of diastereoisomers (four isomers) as crude Nebivolol. The crude Nebivolol is then converted to the salt with hydrochloric acid. After recrystallizations from ethanol are repeated to remove another pair of isomers, racemic Nebivolol is obtained.

The problem of this method is similar to that of the previous method, that is, the reaction conditions are harsh, and the separation of the key intermediates needs column chromatography, thus it is difficult to apply this method to large-scale industrial production.
(3) D-Nebivolol and L-Nebivolol are Synthesized Respectively, and the D-Isomer and L-Isomer are Mixed in Equal Amounts to Give Racemic Nebivolol. The Methods for Synthesis of Optical Isomers of Nebivolol Mainly Include the Following:
Patents EP0334429 and U.S. Pat. No. 6,545,040 disclose the chroman carboxylic acid is resolved to the corresponding S-chroman carboxylic acid and R-chroman carboxylic acid, and the following procedure is used to synthesize L-Nebivolol,

The above method is still a method derived from Janssen patent EP145067. Although an optically pure chroman carboxylic acid obtained by chiral separation is used, the subsequent step of forming an epoxide intermediate using trimethylsulfoxonium iodide in the presence of sodium hydride still produces two diastereoisomers in unequal amounts, thus chromatographic separation is likewise required in order to obtain two optically pure epoxide intermediates.
The literatures (Tetrahedron, 56, 6339-6344, 2000 and Chinese Journal of Organic Chemistry 28, 511-514, 2008) have reported the synthesis using 1-(6-fluoro-benzopyranyl)ethane-1,2-diol as key intermediate, in which Sharpless asymmetric epoxidation reaction is utilized. The synthetic route is as follows

But these methods have long synthetic routes, the intermediates are oil, separation and purification need column chromatography, and reagents are expensive, thus it is difficult to apply the methods to industrial production.
Furthermore, the following multi-step reaction is also required to convert the intermediate 1-[6-fluoro-(2S)-3,4-dihydro-2H-benzopyran-2-yl]-(1R)-1,2-diol to 1-[6-fluoro-(2R)-3,4-dihydro-2H-benzopyran-2-yl]-(1R)-1,2-diol to obtain the SRRR-Nebivolol in desired configuration:

Patents CN1834093A and CN1978442 disclose the synthesis using glyceraldehyde acetonide as raw material: reaction of D-glyceraldehyde acetonide with 5-fluoro-2-hydroxyacetophenone via Kabbe condensation and then separation by column chromatography give two chroman diol isomers (S,R) and (R, R).

The optically active dextro-rotatory SRRR-Nebivolol can be obtained by selectively sulfonylating the two chroman diols (S,R) and (R,R) isomers with p-toluenesulfonyl chloride, respectively, followed by amination.
In summary, according to the prior art literature to date, it can be found that Nebivolol synthesis still has many technical defects. For example, Janssen's method, although has shorter synthetic route, requires separation of two diastereomeric epoxide intermediates by preparative HPLC, while other methods often face to more synthetic steps and the issue of separating isomers. Therefore, there is a need to develop a highly efficient, low-cost, new method for preparation of Nebivolol and its optical isomers, which is consistent with the requirements of industrialization.
Contents of the Invention
Throughout the invention, the following terms have the meanings as indicated below.
The term “alkyl”, whether it is used alone or in combination with other groups, represents a straight or branched monovalent saturated hydrocarbon group consisting of carbon atom and hydrogen atom. “C1-6 alkyl” represents straight or branched alkyl having 1-6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, and n-hexyl.
The term “alkylene”, whether it is used alone or in combination with other groups, represents a straight or branched divalent saturated hydrocarbon group consisting of carbon atom and hydrogen atom. “C1-6 alkylene” represents straight or branched alkylene having 1-6 carbon atoms, such as methylene, ethylene, and the like.
The term “alkoxy”, whether it is used alone or in combination with other groups, represents group RA—O—, wherein RA represents alkyl as defined above. “C1-6 alkoxy” represents group RA—O—, wherein RA represents C1-6 alkyl as defined above.
“Halo” or “Halogen” represents fluoro, chloro, bromo or iodo.
“Haloalkyl” represents alkyl as defined above which is substituted with one or more halogens, e.g., trifluoromethyl.
“Nitro” represents —NO2.
“Aryl” represents monocyclic or fused bicyclic aromatic ring containing carbon atoms. “C5-10 aryl” represents aryl having 5-10 carbon atoms. For example, C5-10 aryl may be phenyl or naphthyl.
“Substituted aryl” represents aryl which is substituted with alkyl, alkoxy, halo, haloalkyl or nitro as defined above.
“Aralkyl” represents alkyl as defined above which is substituted with aryl as defined above.
“Substituted aralkyl” represents aralkyl which is substituted with alkyl, alkoxy, halo, haloalkyl or nitro as defined above.
“Aralkoxy” represents alkoxy as defined above which is substituted with aryl as defined above.
“Substituted aralkoxy” represents aralkoxy which is substituted with alkyl, alkoxy, halo, haloalkyl or nitro as defined above.
In an aspect, the present invention provides a process for preparation of formula III

wherein R is hydroxy-protecting group, which is selected from alkyl, haloalkyl, aralkyl, alkoxyalkyl, allyl, or silyl protective group, such as t-BuMe2Si, t-BuPh2Si, (i-Pr)3Si, Et3Si, allyl, methoxymethyl, benzyl or —CH2Ar, wherein Ar is unsubstituted or substituted aryl, such as p-methoxyphenyl or halogen-substituted phenyl,
the process comprising the following steps:

step a): reacting the compound of formula XIV, wherein R is hydroxy-protecting group as described above and X is halogen, with 3-(tri-substituted silyl)-prop-2-yne-1-lithium to give the compound of formula XV, wherein each of R1, R2 and R3 is independently selected from alkyl or aryl, such as methyl, tert-butyl or phenyl;
step b): removing the silyl protective group at the terminal of alkynyl in the compound of formula XV to give the compound of formula XVI, wherein R is defined as above;
step c): reacting the compound of formula XVI with paraformaldehyde in the presence of base or organometallic reagent to give the compound of formula III, wherein R is defined as above; and
optionally step d): to the compound of formula III obtained by step c), adding non-polar organic solvent, such as n-hexane, n-heptane, petroleum ether, diethyl ether, isopropyl ether or tert-butyl methyl ether, or a mixture of any two or more of them, stirring at low temperature such as 0° C. to −20° C., followed by crystallization and filtration, to yield the compound of formula III as solid.
In a preferred embodiment, the reaction of step a) is carried out in organic aprotic solvent, such as methyltetrahydrofuran, tetrahydrofuran, dioxane, diethyl ether, tert-butyl methyl ether or toluene, and the reaction temperature is −100° C. to 60° C.
In another preferred embodiment, the reaction of step b) is carried out in the presence of base, acid, or a salt containing fluorine, preferably in the presence of base, said base is selected from alkali metal or alkali earth metal hydroxide or carbonate, such as NaOH, KOH, Na2CO3, K2CO3, the solvent used in the reaction is selected from protic solvent, such as water, methanol, ethanol, or a mixture of any two or more of them, and the reaction temperature is −100° C. to 80° C.
In another preferred embodiment, the base in step c) is selected from metal hydride or organic base, such as NaNH2 or KNH2, the organometallic reagent is selected from BuLi, t-BuLi, s-BuLi, LDA or Grignard reagent, such as MeMgX, EtMgX, BuMgX, i-PrMgX, wherein X is Br, I or Cl, the solvent used in the reaction is organic aprotic solvent, such as tetrahydrofuran, methyltetrahydrofuran, toluene, dioxane, diethyl ether, isopropyl ether, tert-butyl methyl ether, toluene, or a mixture of any two or more of them, and the reaction temperature is −100° C. to 100° C.
In another preferred embodiment, the organic solvent in step d) is organic aprotic solvent, such as n-heptane, n-hexane, petroleum ether, diethyl ether, isopropyl ether, tert-butyl methyl ether, or a mixture of any two or more of them.
In a further preferred embodiment, the reaction of step a) is carried out in organic aprotic solvent, such as methyltetrahydrofuran, tetrahydrofuran, dioxane, diethyl ether, tert-butyl methyl ether or toluene;
the reaction of step b) is carried out in the presence of base, acid, or a salt containing fluorine, preferably in the presence of base, said base is selected from alkali metal or alkali earth metal hydroxide or carbonate, such as NaOH, KOH, Na2CO3, K2CO3, the solvent used in the reaction is selected from protic solvent, such as water, methanol, ethanol, or a mixture of any two or more of them; and
the base in step c) is selected from metal hydride or organic base, such as NaNH2 or KNH2, the organometallic reagent is selected from BuLi, t-BuLi, s-BuLi, LDA or Grignard reagent, such as MeMgX, EtMgX, BuMgX, i-PrMgX, wherein X is Br, I or Cl, the solvent used in the reaction is organic aprotic solvent, such as tetrahydrofuran, methyltetrahydrofuran, toluene, dioxane, diethyl ether, isopropyl ether, tert-butyl methyl ether, toluene, or a mixture of any two or more of them.
A skilled person in the art will understand that, in above process for preparation of the compound of formula III, the reaction product of any one of step a) to step c) or d) can be used as starting material to perform subsequent steps described above to prepare the compound of formula III. For example, the compounds of formula (XV) can be used as starting material to perform steps b) to c) or d) described above to prepare the compound of formula III, or the compounds of formula (XVI) can be used as starting material to perform step c) or d) described above to prepare the compound of formula III.
In another aspect, the present invention provides the compound of formula III,

wherein R is hydroxy-protecting group, which is selected from alkyl, haloalkyl, aralkyl, alkoxyalkyl, allyl, or silyl protective group, such as t-BuMe2Si, t-BuPh2Si, (i-Pr)3Si, Et3Si, allyl, methoxymethyl, benzyl or —CH2Ar, wherein Ar is unsubstituted or substituted aryl, such as p-methoxyphenyl or halogen-substituted phenyl.
In another aspect, the present invention provides a process for preparation of racemic Nebivolol of formula I,

wherein I (S*R*R*R*) represents racemate, which is a racemic mixture consisting of equimolar amounts of D-Nebivolol Ia (SRRR) and the enantioner thereof L-Nebivolol Ib (RSSS) having the following configurations;

the process comprising the following steps:
1) reducing the compound of formula III with metal composite hydride to give the compound of formula IV1 in trans-configuration;
and optionally the following step: to the resulting compound of formula IV1, adding non-polar organic solvent, such as n-hexane, n-heptane, petroleum ether, diethyl ether, isopropyl ether or tert-butyl methyl ether, or a mixture of any two or more of them, stirring at low temperature such as 0° C. to −20° C., followed by crystallization and filtration, to yield the compound of formula IV1 as solid,

wherein R is hydroxy-protecting group, which is selected from alkyl, haloalkyl, aralkyl, alkoxyalkyl, allyl, or silyl protective group, such as t-BuMe2Si, t-BuPh2Si, (i-Pr)3Si, Et3Si, methoxymethyl, benzyl or —CH2Ar, wherein Ar is unsubstituted or substituted aryl, such as p-methoxyphenyl or halogen-substituted phenyl,
2) reducing the compound of formula III via selective catalytic hydrogenation to give the compound of formula IV2 in cis-configuration
and optionally the following step: to the resulting compound of formula IV2, adding non-polar organic solvent, such as n-hexane, n-heptane, petroleum ether, diethyl ether, isopropyl ether or tert-butyl methyl ether, or a mixture of any two or more of them, stirring at low temperature such as 0° C. to −20° C., followed by crystallization and filtration, to yield the compound of formula IV2 as solid,

wherein R is defined as above 1),
3) epoxidation of the compound of formula IV1 in trans-configuration and the compound of formula IV2 in cis-configuration in the presence of epoxidating reagent to give epoxide intermediates V and VI, respectively, wherein R is defined as above,

wherein the compound V is racemate, which is a racemic mixture consisting of equimolar amounts of the compound of formula Va and the enantiomer Vb, the relative configuration of which is represented as V (2R*,3R*),

wherein the compound VI is racemate, which is a racemic mixture consisting of equimolar amounts of the compound of formula VIa and the enantiomer VIb, the relative configuration of which is represented as VI (2R*,3S*),

4) deprotecting the compound of formula V and the compound of formula VI, followed by cyclization reaction, to give the intermediate compounds of formula VII (S*/R*) and formula VIII (R*/R*), respectively, wherein R is defined as above,

wherein VII (S*/R*) is racemate, which is a racemic mixture consisting of equimolar amounts of the compound of formula VIIa (S/R) and the enantiomer VIIb (R/S),

wherein VIII (R*/R*) is racemate, which is a racemic mixture consisting of equimolar amounts of the compound of formula VIIIa (R/R) and the enantiomer VIIIb (S/S),

5) sulfonylating the compounds of formula VII and formula VIII with sulfonyl halide of formula M-SO2X (wherein M is alkyl or substituted or unsubstituted aryl, X is halogen) in the presence of catalyst and base, to give the compounds IX (S*/R*) and X (R*/R*), respectively,

wherein IX (S*/R*) is racemate, which is a racemic mixture consisting of equimolar amounts of the compound of formula IXa (S/R) and the enantiomer IXb (R/S),

wherein X (R*/R*) is racemate, which is a racemic mixture consisting of equimolar amounts of the compound of formula Xa (R/R) and the enantiomer Xb (S/S),

6) reacting the compound of formula IX or X with benzyl amine to perform alkylation of amine, to give the corresponding compound XI or XII;

wherein XI (S*/R*) is racemate, which is a racemic mixture consisting of equimolar amounts of the compound of formula XIa (S/R) and the enantiomer XIb (R/S),

wherein XII (R*/R*) is racemate, which is a racemic mixture consisting of equimolar amounts of the compound of formula XIIa (R/R) and the enantiomer XIIb (S/S),

7) cross-coupling reaction of the intermediate compounds IX (S*/R*) and XII (R*/R*) or the intermediate compounds X (R*/R*) and XI (S*/R*) under basic condition, to give the compounds XIII (S*R*R*R*) and XIII′ (S*R*S*S*), wherein the definition of R″ is the same as the above definition of M,

wherein XIII (S*R*R*R*) is racemate, which is a racemic mixture consisting of equimolar amounts of the compound of formula XIIIa (SRRR) and the enantiomer XIIIb (RSSS),

XIII′ (S*R*S*S*) is racemate, which is a racemic mixture consisting of equimolar amounts of the compound of formula XIII′a (SRSS) and the enantiomer XIII′b (RSRR),

8) Forming salt of a mixture of the compounds of formula XIII and formula XIII′, and purifying by recrystallization to remove the isomer XIII′ (S*R*S*S*), to give the intermediate compound XIII (S*R*R*R*),
9) deprotecting the intermediate compound XIII (S*R*R*R*) to yield racemic Nebivolol of formula I

wherein I (S*R*R*R*) is racemate, which is a racemic mixture consisting of equimolar amounts of the compound of formula Ia (SRRR) and the enantiomer Ib (RSSS).
In an embodiment, in step 1), the metal composite hydride used as reducing agent is LiAlH4 or sodium bis(2-methoxyethoxy)aluminum dihydride, the solvent used in the reaction is organic aprotic solvent, such as tetrahydrofuran, methyltetrahydrofuran, toluene, dioxane, diethyl ether, isopropyl ether, tert-butyl methyl ether, toluene, or a mixture of any two or more of them, and the reaction temperature is −100° C. to 60° C.
In an embodiment, in step 2), the catalyst used in the selective catalytic hydrogenation is selected from Lindlar catalyst or P-2 nickel boride/ethylenediamine catalyst.
In an embodiment, in step 3), epoxidation of the compound of formula IV1 in trans-configuration or the compound of formula IV2 in cis-configuration can be carried out by using the epoxidation methods commonly used in the art, for example, the epoxidating reagent which can be used in the reaction is selected from organic peroxy-acid, such as MCPBA, trifluoroperacetic acid, dimethyldioxirane (DMDO), a mixture of hydrogen peroxide and acetic acid, and a mixture of VO(acac)2 and tert-butyl hydroperoxide, and the system of pyridine-H2O2 in the presence of catalytic amount of methylrhenium trioxide (MTO), the solvent in the reaction is organic aprotic solvent, such as methylene dichloride, chloroform, tetrahydrofuran, toluene, or a mixture of any two or more of them, and the reaction temperature is −50° C. to 50° C.
In an embodiment, in step 4), the deprotection can be carried out by the conventional methods in the field of organic chemistry to remove the hydroxy-protecting group, for example, by hydrogenolysis in the presence of catalyst to remove benzyl protective group, and cyclization is carried out in the presence of base; the catalyst used in the hydrogenolysis is Pd catalyst, such as Pd/C, Pd(OH)2, Pd(OAc)2, PdCl2, Pd; the base used in the cyclization is selected from alkali metal and alkaline earth metal hydroxide or carbonate, alkoxide, or organic base, such as NaOH, KOH, K2CO3, NaOMe, DBU; or the deprotection and the cyclization are carried out by hydrogenolysis using Pd/C as catalyst under basic condition to simultaneously remove benzyl protective group and perform cyclization, to directly give the cyclization product.
In an embodiment, in step 5), the sulfonyl halide used in the sulfonylation can be arylsulfonyl chloride or substituted arylsulfonyl chloride or alkylsulfonyl chloride, such as p-toluenesulfonyl chloride, phenylsulfonyl chloride, p-halophenylsulfonyl chloride, p-nitrophenylsulfonyl chloride, o-nitrophenylsulfonyl chloride or methylsulfonyl chloride; no catalyst is used or an appropriate amount of acylation catalyst is used in the reaction, and the catalyst can be dialkyltin oxides, DMAP, such as dibutyltin oxide and 2,2-dibutyl-1,3,2-dioxastannolane; the base used in the reaction can be conventional organic base, such as pyridine, organic tertiary amine, such as triethylamine or diisopropylethylamine, the solvent in the reaction is organic aprotic solvent, such as methylene dichloride, chloroform, methyltetrahydrofuran, tetrahydrofuran, pyridine, toluene, ethyl acetate, acetonitrile, DMF, DMA, or a mixture of any two or more of them, and the reaction temperature is −50° C. to 50° C.
In an embodiment, in step 6), alkylation of amine is carried out by reaction of benzyl amine with corresponding sulfonate, and the molar ratio of the benzyl amine used and the corresponding sulfonate substrate is 1/1 to 10/1, the solvent in the reaction is organic aprotic solvent, such as methylene dichloride, chloroform, methyltetrahydrofuran, tetrahydrofuran, pyridine, toluene, ethyl acetate, acetonitrile, DMF, DMA, or a mixture of any two or more of them, and the reaction temperature is −25° C. to 150° C.
In an embodiment, in step 7), the base used in the cross-coupling reaction can be selected from inorganic base, such as K2CO3, Na2CO3, or organic tertiary amine, such as triethylamine or diisopropylethylamine, the solvent in the reaction is organic protic solvent, such as ethanol, propanol, isopropanol, or organic polar aprotic solvent, such as acetone, butanone, toluene, tetrahydrofuran, dimethylformamide, or a mixture of any two or more of these solvents, and the reaction temperature is −25° C. to 150° C.
In an embodiment, in step 9), the catalyst used in the deprotection reaction is Pd catalyst, such as Pd/C, Pd(OH)2, Pd(OAc)2, PdCl2, Pd; the solvent in the reaction is alcohol or ester or ether, or a mixture of any two or more of these solvents, such as methanol or ethanol.
In a preferred embodiment, in step 1), the metal composite hydride used as reducing agent is LiAlH4 or sodium bis(2-methoxyethoxy)aluminum dihydride, the solvent used in the reaction is organic aprotic solvent, such as methyltetrahydrofuran, tetrahydrofuran, methyltetrahydrofuran, toluene, dioxane, diethyl ether, isopropyl ether, tert-butyl methyl ether, toluene, or a mixture of any two or more of them;
in step 2), the catalyst used in the selective catalytic hydrogenation is selected from Lindlar catalyst or P-2 nickel boride/ethylenediamine catalyst;
in step 3), epoxidation of the compound of formula IV1 in trans-configuration or the compound of formula IV2 in cis-configuration can be carried out by using the epoxidation methods commonly used in the art, for example, the epoxidating reagent which can be used in the reaction is selected from organic peroxy-acid, such as MCPBA, trifluoroperacetic acid, dimethyldioxirane (DMDO), a mixture of hydrogen peroxide and acetic acid, and a mixture of VO(acac)2 and tert-butyl hydroperoxide, and the system of pyridine-H2O2 in the presence of catalytic amount of methylrhenium trioxide (MTO), and the solvent in the reaction is organic aprotic solvent, such as methylene dichloride, chloroform, methyltetrahydrofuran, tetrahydrofuran, toluene, or a mixture of any two or more of them;
in step 4), the deprotection can be carried out by the conventional methods in the field of organic chemistry to remove the hydroxy-protecting group, for example, by hydrogenolysis in the presence of catalyst to remove benzyl protective group, and cyclization is carried out in the presence of base; the catalyst used in the hydrogenolysis is Pd catalyst, such as Pd/C, Pd(OH)2, Pd(OAc)2, PdCl2, Pd; the base used in the cyclization is selected from alkali metal and alkaline earth metal hydroxide or carbonate, alkoxide, or organic base, such as NaOH, KOH, K2CO3, NaOMe, DBU; or the deprotection and the cyclization are carried out by hydrogenolysis using Pd/C as catalyst under basic condition to simultaneously remove benzyl protective group and perform cyclization, to directly give the cyclization product;
in step 5), the sulfonyl halide used in the sulfonylation can be arylsulfonyl chloride or substituted arylsulfonyl chloride or alkylsulfonyl chloride, such as p-toluenesulfonyl chloride, phenylsulfonyl chloride, p-halophenylsulfonyl chloride, p-nitrophenylsulfonyl chloride or o-nitrophenylsulfonyl chloride or methylsulfonyl chloride; no catalyst is used or an appropriate amount of acylation catalyst is used in the reaction, and the catalyst can be dialkyltin oxides, DMAP, such as dibutyltin oxide and 2,2-dibutyl-1,3,2-dioxastannolane; the base used in the reaction can be conventional organic base, such as pyridine, organic tertiary amine, such as triethylamine or diisopropylethylamine, the solvent in the reaction is organic aprotic solvent, such as methylene dichloride, chloroform, tetrahydrofuran, methyltetrahydrofuran, pyridine, toluene, acetonitrile, ethyl acetate, DMF, DMA, or a mixture of any two or more of them;
in step 6), alkylation of amine is carried out by reaction of benzyl amine with corresponding sulfonate, the solvent in the reaction is organic aprotic solvent, such as methylene dichloride, chloroform, methyltetrahydrofuran, tetrahydrofuran, pyridine, toluene, ethyl acetate, acetonitrile, DMF, DMA, or a mixture of any two or more of them;
in step 7), the base used in the cross-coupling reaction can be selected from inorganic base, such as K2CO3, Na2CO3, or organic tertiary amine, such as triethylamine or diisopropylethylamine, the solvent in the reaction is organic protic solvent, such as ethanol, propanol, isopropanol, or organic polar aprotic solvent, such as acetone, butanone, toluene, tetrahydrofuran, dimethylformamide, or a mixture of any two or more of these solvents; and
in step 9), the catalyst used in the deprotection reaction is Pd catalyst, such as Pd/C, Pd(OH)2, Pd(OAc)2, PdCl2, Pd, the solvent in the reaction is alcohol, ester or ether, or a mixture of any two or more of these solvents, such as methanol or ethanol.
A skilled person in the art will understand that, in above process for preparation of the compound of formula I, the reaction product of any one of step 1) to step 9) can be used as starting material to perform subsequent steps described above to prepare the compound of formula I. For example, the compounds of formula IV1 and formula IV2 can be used as starting materials to perform steps 2) to 9) described above to obtain racemic Nebivolol of formula I, or the compounds of formula IX and formula XII can be used as starting materials to perform steps 7) to 9) described above to obtain racemic Nebivolol of formula I.
In another aspect, the present invention provides a process for preparation of formula IV1,

wherein R is hydroxy-protecting group, which is selected from aralkyl, alkoxyalkyl, allyl or silyl protective group, such as t-BuMe2Si, t-BuPh2Si, (i-Pr)3Si, Et3Si, methoxymethyl, benzyl or —CH2Ar, wherein Ar is unsubstituted or substituted aryl, such as p-methoxyphenyl or halogen-substituted phenyl,
the process comprising the following steps:
reducing the compound of formula III with metal composite hydride to give the compound of formula IV1, and optionally the following step: to the resulting compound of formula IV1, adding non-polar organic solvent, such as n-hexane, n-heptane, petroleum ether, diethyl ether, isopropyl ether or tert-butyl methyl ether, or a mixture of any two or more of them, stirring at low temperature such as 0° C. to −20° C., followed by crystallization and filtration, to yield the compound of formula IV1 as solid,

wherein R is defined as above.
In a preferred embodiment, in the above process, the metal composite hydride used as reducing agent is LiAlH4 or sodium bis(2-methoxyethoxy)aluminum dihydride, the solvent used in the reaction is organic aprotic solvent, such as tetrahydrofuran, methyltetrahydrofuran, toluene, dioxane, diethyl ether, isopropyl ether, tert-butyl methyl ether, toluene, or a mixture of any two or more of them.
In another aspect, the present invention provides a process for preparation of formula IV2,

wherein R is hydroxy-protecting group, which is selected from aralkyl, alkoxyalkyl, allyl or silyl protective group, such as t-BuMe2Si, t-BuPh2Si, (i-Pr)3Si, Et3Si, methoxymethyl, benzyl or —CH2Ar, wherein Ar is unsubstituted or substituted aryl, such as p-methoxyphenyl or halogen-substituted phenyl,
the process comprising the following steps:
reducing the compound of formula III via selective catalytic hydrogenation to give the compound of formula IV2 in cis-configuration, and optionally the following step: to the resulting compound of formula IV2, adding non-polar organic solvent, such as n-hexane, n-heptane, petroleum ether, diethyl ether, isopropyl ether or tert-butyl methyl ether, or a mixture of any two or more of them, stirring at low temperature such as 0° C. to −20° C., followed by crystallization and filtration, to yield the compound of formula IV2 as solid,

wherein R is defined as above.
In a preferred embodiment, in the above process, the catalyst used in the selective catalytic hydrogenation is selected from Lindlar catalyst or P-2 nickel boride/ethylenediamine catalyst.
In another aspect, the present invention provides a process for preparation of the compound of formula VII (S*/R*),

wherein VII (S*/R*) is racemate, which is a racemic mixture consisting of equimolar amounts of the compound of formula VIIa (S/R) and the enantiomer VIIb (R/S),

the process comprising the following steps:
3) epoxidation of the compound of formula IV1 in trans-configuration in the presence of epoxidating reagent to give epoxide intermediate V

wherein R is hydroxy-protecting group, which is selected from alkyl, haloalkyl, aralkyl, alkoxyalkyl, allyl or silyl protective group, such as t-BuMe2Si, t-BuPh2Si, (i-Pr)3Si, Et3Si, methoxymethyl, benzyl or —CH2Ar, wherein Ar is unsubstituted or substituted aryl, such as p-methoxyphenyl or halogen-substituted phenyl, but R shown in the follow formulae is represented by benzyl (Bn) as an example,

wherein the compound V is racemate, which is a racemic mixture consisting of equimolar amounts of the compound of formula Va and the enantiomer Vb, the relative configuration of which is represented as V (2R*,3R*)

4) deprotecting the compound of formula V (2R*,3R*), followed by cyclization reaction, to give the intermediate compounds of formula VII (S*/R*), wherein R is defined as above, but R shown in the follow formulae is represented by benzyl (Bn) as an example,

wherein VII (S*/R*) is racemate, which is a racemic mixture consisting of equimolar amounts of the compound of formula VIIa (S/R) and the enantiomer VIIb (R/S),

In a preferred embodiment, the reaction condition, solvent, and the like in the steps 3) and 4) are as described above.
In another aspect, the present invention provides a process for preparation of the compound of formula VIII (R*/R*),

wherein VIII (R*/R*) is racemate, which is a racemic mixture consisting of equimolar amounts of the compound of formula VIIIa (R/R) and the enantiomer VIIIb (S/S),

the process comprising the following steps:
3) epoxidation of the compound of formula IV2 in cis-configuration in the presence of epoxidating reagent to give epoxide intermediate VI,

wherein R is hydroxy-protecting group, which is selected from alkyl, haloalkyl, aralkyl, alkoxyalkyl, allyl or silyl protective group, such as t-BuMe2Si, t-BuPh2Si, (i-Pr)3Si, Et3Si, methoxymethyl, benzyl or —CH2Ar, wherein Ar is unsubstituted or substituted aryl, such as p-methoxyphenyl or halogen-substituted phenyl, but R shown in the follow formulae is represented by benzyl (Bn) as an example,

wherein the compound VI is racemate, which is a racemic mixture consisting of equimolar amounts of the compound of formula VIa and the enantiomer VIb, the relative configuration of which is represented as VI (2R*,3S*)

4) deprotecting the compound of formula VI (2R*,3S*), followed by cyclization reaction, to give the intermediate compounds of formula VIII (R*/R*), wherein R is defined as above, but R shown in the follow formulae is represented by benzyl (Bn) as an example,

wherein VIII (R*/R*) is racemate, which is a racemic mixture consisting of equimolar amounts of the compound of formula VIIIa (R/R) and the enantiomer VIIIb (S/S),

In a preferred embodiment, the reaction condition, solvent, and the like in the steps 3) and 4) are as described above.
In another aspect, the present invention provides a process for preparation of racemic Nebivolol of formula I,

wherein I (S*R*R*R*) represents racemate, which is a racemic mixture consisting of equimolar amounts of D-Nebivolol Ia (SRRR) and the enantioner thereof L-Nebivolol Ib (RSSS) having the following configurations

the process comprising the following steps a) to c) or d) and steps 1) to 9):

step a): reacting the compound of formula XIV with 3-(tri-substituted silyl)-prop-2-yne-1-lithium to give the compound of formula XV, wherein each of R1, R2 and R3 is independently selected from alkyl or aryl, such as methyl, tert-butyl or phenyl; R is hydroxy-protecting group, which is selected from alkyl, haloalkyl, aralkyl, alkoxyalkyl, allyl or silyl protective group, such as t-BuMe2Si, t-BuPh2Si, (i-Pr)3Si, Et3Si, methoxymethyl, benzyl or —CH2Ar, wherein Ar is unsubstituted or substituted aryl, such as p-methoxyphenyl or halogen-substituted phenyl, and X is halogen;
step b): removing the silyl protective group at the terminal of alkynyl in the compound of formula XV to give the compound of formula XVI, wherein R is defined as above;
step c): reacting the compound of formula XVI with paraformaldehyde in the presence of base or organometallic reagent to give the compound of formula III, wherein R is defined as above; and
optionally step d): to the compound of formula III obtained by step c), adding non-polar organic solvent, such as n-hexane, n-heptane, petroleum ether, diethyl ether, isopropyl ether or tert-butyl methyl ether, or a mixture of any two or more of them, stirring at low temperature such as 0° C. to −20° C., followed by crystallization and filtration, to yield the compound of formula III as solid;
step 1): reducing the compound of formula III with metal composite hydride to give the compound of formula IV1 in trans-configuration, and optionally the following step: to the resulting compound of formula IV1, adding non-polar organic solvent, such as n-hexane, n-heptane, petroleum ether, diethyl ether, isopropyl ether or tert-butyl methyl ether, or a mixture of any two or more of them, stirring at low temperature such as 0° C. to −20° C., followed by crystallization and filtration, to yield the compound of formula IV1 as solid,

wherein R is defined as above,
step 2): reducing the compound of formula III via selective catalytic hydrogenation to give the compound of formula IV2 in cis-configuration, and optionally the following step: to the resulting compound of formula IV2, adding non-polar organic solvent, such as n-hexane, n-heptane, petroleum ether, diethyl ether, isopropyl ether or tert-butyl methyl ether, or a mixture of any two or more of them, stirring at low temperature such as 0° C. to −20° C., followed by crystallization and filtration, to yield the compound of formula IV2 as solid,

wherein R is defined as above,
step 3): epoxidation of the compound of formula IV1 in trans-configuration and the compound of formula IV2 in cis-configuration in the presence of epoxidating reagent to give epoxide intermediates V and VI, respectively, wherein R is defined as above,

wherein the compound V is racemate, which is a racemic mixture consisting of equimolar amounts of the compound of formula Va and the enantiomer Vb, the relative configuration of which is represented as V (2R*,3R*)

wherein the compound VI is racemate, which is a racemic mixture consisting of equimolar amounts of the compound of formula VIa and the enantiomer VIb, the relative configuration of which is represented as VI (2R*,3S*)

step 4): deprotecting the compound of formula V and the compound of formula VI, followed by cyclization reaction, to give the intermediate compounds of formula VII (S*/R*) and formula VIII (R*/R*), respectively, wherein R is defined as above,

wherein VII (S*/R*) is racemate, which is a racemic mixture consisting of equimolar amounts of the compound of formula VIIa (S/R) and the enantiomer VIIb (R/S),

wherein VIII (R*/R*) is racemate, which is a racemic mixture consisting of equimolar amounts of the compound of formula VIIIa (R/R) and the enantiomer VIIIb (S/S),

step 5): sulfonylating the compounds of formula VII and formula VIII with sulfonyl halide of formula M-SO2X (wherein M is alkyl or substituted or unsubstituted aryl, X is halogen) in the presence of catalyst and base, to give the compounds IX (S*/R*) and X (R*/R*), respectively,

wherein IX (S*/R*) is racemate, which is a racemic mixture consisting of equimolar amounts of the compound of formula IXa (S/R) and the enantiomer IXb (R/S),

wherein X (R*/R*) is racemate, which is a racemic mixture consisting of equimolar amounts of the compound of formula Xa (R/R) and the enantiomer Xb (S/S),

step 6): reacting the compound of formula IX or X with benzyl amine to perform alkylation of amine, to give the corresponding compound XI or XII;

wherein XI (S*/R*) is racemate, which is a racemic mixture consisting of equimolar amounts of the compound of formula XIa (S/R) and the enantiomer XIb (R/S),

wherein XII (R*/R*) is racemate, which is a racemic mixture consisting of equimolar amounts of the compound of formula XIIa (R/R) and the enantiomer XIIb (S/S)

step 7): cross-coupling reaction of the intermediate compounds IX (S*/R*) and XII (R*/R*) or the intermediate compounds X (R*/R*) and XI (S*/R*) under basic condition, to give the compounds XIII (S*R*R*R*) and XIII′ (S*R*S*S*), wherein the definition of R″ is the same as the above definition of

wherein XIII (S*R*R*R*) is racemate, which is a racemic mixture consisting of equimolar amounts of the compound of formula XIIIa (SRRR) and the enantiomer XIIIb (RSSS),

XIII′ (S*R*S*S*) is racemate, which is a racemic mixture consisting of equimolar amounts of the compound of formula XIII′a (SRSS) and the enantiomer XIII′b (RSRR),

step 8): Forming salt of a mixture of the compounds of formula XIII and formula XIII′, and purifying by recrystallization to remove the isomer XIII′ (S*R*S*S*), to give the intermediate compound XIII (S*R*R*R*),
step 9): deprotecting the intermediate compound XIII to yield racemic Nebivolol of formula I

wherein I (S*R*R*R*) is racemate, which is a racemic mixture consisting of equimolar amounts of the compound of formula Ia (SRRR) and the enantiomer Ib (RSSS).
Regarding this process for preparation of the compound of formula I, the reaction conditions, solvents, reagents used in steps a) to c) and steps 1) to 9) are as described above.
In a further preferred embodiment, in step a), the reaction is carried out in organic aprotic solvent, such as methyltetrahydrofuran, tetrahydrofuran, dioxane, diethyl ether, tert-butyl methyl ether or toluene;
in step b), the reaction is carried out in the presence of base, acid, or a salt containing fluorine, preferably in the presence of base, said base is selected from alkali metal or alkali earth metal hydroxide or carbonate, such as NaOH, KOH, Na2CO3, K2CO3, the solvent used in the reaction is selected from protic solvent, such as water, methanol, ethanol, or a mixture of any two or more of them;
in step c), the base is selected from metal hydride or organic base, such as NaNH2 or KNH2, the organometallic reagent is selected from BuLi, t-BuLi, s-BuLi, LDA or Grignard reagent, such as MeMgX, EtMgX, BuMgX, i-PrMgX, wherein X is Br, I or Cl, the solvent used in the reaction is organic aprotic solvent, such as tetrahydrofuran, methyltetrahydrofuran, toluene, dioxane, diethyl ether, isopropyl ether, tert-butyl methyl ether, toluene, or a mixture of any two or more of them;
in step 1), the metal composite hydride used as reducing agent is LiAlH4 or sodium bis(2-methoxyethoxy)aluminum dihydride, the solvent used in the reaction is organic aprotic solvent, such as tetrahydrofuran, methyltetrahydrofuran, toluene, dioxane, diethyl ether, isopropyl ether, tert-butyl methyl ether, toluene, or a mixture of any two or more of them;
in step 2), the catalyst used in the selective catalytic hydrogenation is selected from Lindlar catalyst or P-2 nickel boride/ethylenediamine catalyst;
in step 3), epoxidation of the compound of formula IV1 in trans-configuration or the compound of formula IV2 in cis-configuration can be carried out by using the epoxidation methods commonly used in the art, for example, the epoxidating reagent which can be used in the reaction is selected from organic peroxy-acid, such as MCPBA, trifluoroperacetic acid, dimethyldioxirane (DMDO), a mixture of hydrogen peroxide and acetic acid, and a mixture of VO(acac)2 and tert-butyl hydroperoxide, and the system of pyridine-H2O2 in the presence of catalytic amount of methylrhenium trioxide (MTO), and the solvent in the reaction is organic aprotic solvent, such as methylene dichloride, chloroform, tetrahydrofuran, toluene, or a mixture of any two or more of them;
in step 4), the deprotection can be carried out by the conventional methods in the field of organic chemistry to remove the hydroxy-protecting group, for example, by hydrogenolysis in the presence of catalyst to remove benzyl protective group, and cyclization is carried out in the presence of base; the catalyst used in the hydrogenolysis is Pd catalyst, such as Pd/C, Pd(OH)2, Pd(OAc)2, PdCl2, Pd; the base used in the cyclization is selected from alkali metal and alkaline earth metal hydroxide or carbonate, alkoxide, or organic base, such as NaOH, KOH, K2CO3, NaOMe, DBU; or the deprotection and the cyclization are carried out by hydrogenolysis using Pd/C as catalyst under basic condition to simultaneously remove benzyl protective group and perform cyclization, to directly give the cyclization product;
in step 5), the sulfonyl halide used in the sulfonylation can be arylsulfonyl chloride or substituted arylsulfonyl chloride or alkylsulfonyl chloride, such as p-toluenesulfonyl chloride, phenylsulfonyl chloride, p-halophenylsulfonyl chloride, p-nitrophenylsulfonyl chloride, o-nitrophenylsulfonyl chloride or methylsulfonyl chloride; no catalyst is used or an appropriate amount of acylation catalyst is used in the reaction, and the catalyst can be dialkyltin oxides, DMAP, such as dibutyltin oxide and 2,2-dibutyl-1,3,2-dioxastannolane; the base used in the reaction can be conventional organic base, such as pyridine, organic tertiary amine, such as triethylamine or diisopropylethylamine, the solvent in the reaction is organic aprotic solvent, such as methylene dichloride, chloroform, methyltetrahydrofuran, tetrahydrofuran, pyridine, toluene, ethyl acetate, acetonitrile, DMF, DMA, or a mixture of any two or more of them;
in step 6), alkylation of amine is carried out by reaction of benzyl amine with corresponding sulfonate, the solvent in the reaction is organic aprotic solvent, such as methylene dichloride, chloroform, methyltetrahydrofuran, tetrahydrofuran, pyridine, toluene, ethyl acetate, acetonitrile, DMF, DMA, or a mixture of any two or more of them;
in step 7), the base used in the cross-coupling reaction can be selected from inorganic base, such as K2CO3, Na2CO3, or organic tertiary amine, such as triethylamine or diisopropylethylamine, the solvent in the reaction is organic protic solvent, such as ethanol, propanol, isopropanol, or organic polar aprotic solvent, such as acetone, butanone, toluene, tetrahydrofuran, dimethylformamide, or a mixture of any two or more of these solvents; and
in step 9), the catalyst used in the deprotection reaction is Pd catalyst, such as Pd/C, Pd(OH)2, Pd(OAc)2, PdCl2, Pd, the solvent in the reaction is alcohol, ester or ether, or a mixture of any two or more of these solvents, such as methanol or ethanol.
A skilled person in the art will understand that, in above process for preparation of the compound of formula I, the reaction product of any one of step a) to step 9) can be used as starting material to perform subsequent steps described above to prepare the compound of formula I. For example, the compounds of formula XV can be used as starting material to perform steps b) to 9) described above, or the compounds of formula XVI can be used as starting material to perform steps c) to 9) described above, to obtain racemic Nebivolol of formula I.
In another aspect, the present invention provides a process for preparation of D-Nebivolol (formula Ia),

the process comprising the following steps:
3′) asymmetric epoxidation of the compound of formula IV1 and the compound of formula IV2 to give intermediate compounds Va and VIa, respectively, wherein R is hydroxy-protecting group, which is selected from alkyl, haloalkyl, aralkyl, alkoxyalkyl, allyl, or silyl protective group, such as t-BuMe2Si, t-BuPh2Si, (i-Pr)3Si, Et3Si, methoxymethyl, benzyl or —CH2Ar, wherein Ar is unsubstituted or substituted aryl, such as p-methoxyphenyl or halogen-substituted phenyl;

4′) deprotecting the intermediate compounds Va and VIa, followed by cyclization, to give the intermediate compounds VIIa and VIIIa, respectively, wherein R is defined as above,

5′) sulfonating the intermediate compounds VIIa and VIIIa with sulfonyl halide of formula M-SO2X (wherein M is alkyl or substituted or unsubstituted aryl, X is halogen) in the presence of catalyst and base, to give the intermediate compounds IXa and Xa

6′) reacting the intermediate compound IXa or the intermediate compound Xa with benzyl amine to perform alkylation of amine, to give the corresponding compound XIa or XIIa;

7′) cross-coupling reaction of the intermediate compounds IXa and XIIa or the intermediate compounds Xa and XIa under basic condition, to give the intermediate compounds XIIIa, wherein the definition of Ar′ is the same as the above definition of M,

and optionally converting the intermediate compound XIIIa to the hydrochloride thereof,
8′) deprotecting the intermediate compound XIIIa to give D-Nebivolol (formula Ia),

or converting the hydrochloride of the intermediate compound XIIIa to the intermediate compound XIIIa in free form by neutralization with base, followed by deprotection to give D-Nebivolol (formula Ia).
In another aspect, the present invention provides a process for preparation of L-Nebivolol (formula Ib),

the process comprising the following steps:
3″) asymmetric epoxidation of the compound of formula IV1 and the compound of formula IV2 to give intermediate compounds Vb and VIb, respectively, wherein R is hydroxy-protecting group, which is selected from alkyl, haloalkyl, aralkyl, alkoxyalkyl, allyl, or silyl protective group, such as t-BuMe2Si, t-BuPh2Si, (i-Pr)3Si, Et3Si, methoxymethyl, benzyl or —CH2Ar, wherein Ar is unsubstituted or substituted aryl, such as p-methoxyphenyl or halogen-substituted phenyl,

4″) deprotecting the intermediate compounds Vb and VIb, followed by cyclization, to give the intermediate compounds VIIb and VIIIb, wherein R is defined as above,

5″) sulfonating the intermediate compounds VIIb and VIIIb with sulfonyl halide of formula M-SO2X (wherein M is alkyl or substituted or unsubstituted aryl, X is halogen) in the presence of catalyst and base, to give the intermediate compounds IXb and Xb,

6″) reacting the intermediate compound IXb or the intermediate compound Xb with benzyl amine to perform alkylation of amine, to give the intermediate compounds XIb or XIIb

7″) cross-coupling reaction of the intermediate compounds IXb and XIIb or the intermediate compounds Xb and XIb under basic condition, to give the intermediate compounds XIIIb, wherein the definition of Ar′ is the same as the above definition of M,

and optionally converting the intermediate compound XIIIb to the hydrochloride thereof,
8″) deprotecting the intermediate compound XIIIb to give L-Nebivolol (formula Ib),

or converting the hydrochloride of the intermediate compound XIIIb to the intermediate compound XIIIb in free form by neutralization with base, followed by deprotection to give L-Nebivolol (formula Ib).
In an embodiment of preparing the compound of formula Ia, in step 3′), Sharpless asymmetric epoxidation is used, and the chiral catalyst used in the reaction is D-(−)-diethyl tartrate or D-(−)-diisopropyl tartrate, the reagent in the reaction is titanium tetraisopropoxide, tert-butyl hydroperoxide or cumene hydroperoxide, the solvent in the reaction is methylene dichloride, 3 A or 4 A molecular sieve is added into the reaction system, and the reaction temperature is −45° C. to 50° C.
In an embodiment of preparing the compound of formula Ib, in step 3″), Sharpless asymmetric epoxidation is used, and the chiral catalyst used in the reaction is L-(+)-diethyl tartrate or L-(+)-diisopropyl tartrate, the reagent in the reaction is titanium tetraisopropoxide, tert-butyl hydroperoxide or cumene hydroperoxide, the solvent in the reaction is methylene dichloride, 3 A or 4 A molecular sieve is added into the reaction system, and the reaction temperature is −45° C. to 50° C.
In the process for preparing the compound of formula Ia or Ib, in step 4′) or step 4″), the deprotection can be carried out by the conventional methods in the field of organic chemistry to remove the hydroxy-protecting group, for example, by hydrogenolysis in the presence of catalyst to remove benzyl protective group, and cyclization is carried out in the presence of base; the catalyst used in the hydrogenolysis is Pd catalyst, such as Pd/C, Pd(OH)2, Pd(OAc)2, PdCl2, Pd; the base used in the cyclization is selected from alkali metal and alkaline earth metal hydroxide or carbonate, alkoxide, or organic heterocyclic base, such as NaOH, KOH, K2CO3, NaOMe, DBU; or the deprotection and the cyclization are carried out by hydrogenolysis using Pd/C as catalyst under basic condition to simultaneously remove benzyl protective group and perform cyclization, to directly give the cyclization product.
In the process for preparing the compound of formula Ia or Ib, in step 5′) or step 5″), the sulfonyl halide used in the sulfonylation can be arylsulfonyl chloride or substituted arylsulfonyl chloride or alkylsulfonyl chloride, such as p-toluenesulfonyl chloride, phenylsulfonyl chloride, p-halophenylsulfonyl chloride, p-nitrophenylsulfonyl chloride, o-nitrophenylsulfonyl chloride or methylsulfonyl chloride; no catalyst is used or an acylation catalyst is used in the reaction, and the catalyst used can be dialkyltin oxides, DMAP, such as dibutyltin oxide and 2,2-dibutyl-1,3,2-dioxastannolane; the base used in the reaction can be conventional organic base, such as pyridine, organic tertiary amine, such as triethylamine or diisopropylethylamine, the solvent in the reaction is organic aprotic solvent, such as methylene dichloride, chloroform, methyltetrahydrofuran, tetrahydrofuran, pyridine, toluene, ethyl acetate, acetonitrile, DMF, DMA, or a mixture of any two or more of them, and the reaction temperature is −5 to 50° C.
In the process for preparing the compound of formula Ia or Ib, in step 6′) or step 6″), alkylation of amine is carried out by reaction of benzyl amine with corresponding sulfonate, the solvent in the reaction is organic aprotic solvent, such as methylene dichloride, chloroform, methyltetrahydrofuran, tetrahydrofuran, pyridine, toluene, ethyl acetate, acetonitrile, DMF, DMA, or a mixture of any two or more of them, and the reaction temperature is −25° C. to 150° C.
In the process for preparing the compound of formula Ia or Ib, in step 7′) or step 7″), the base used in the cross-coupling reaction can be selected from inorganic base, such as K2CO3, Na2CO3, or organic tertiary amine, such as triethylamine or diisopropylethylamine, the solvent in the reaction is organic protic solvent, such as ethanol, propanol, isopropanol, or organic polar aprotic solvent, such as acetone, butanone, toluene, tetrahydrofuran, dimethylformamide, or a mixture of any two or more of these solvents, and the reaction temperature is −25° C. to 150° C.
In the process for preparing the compound of formula Ia or Ib, in step 8′) or step 8″), the catalyst used in the deprotection reaction is Pd catalyst, such as Pd/C, Pd(OH)2, Pd(OAc)2, PdCl2, Pd, the solvent in the reaction is alcohol, ester or ether, or a mixture of any two or more of these solvents, such as methanol or ethanol.
In an embodiment, the step of converting the intermediate compound XIIIa or the intermediate compound XIIIb to the hydrochloride thereof is carried out by adding hydrochloric acid to the intermediate compound, such as 1N hydrochloric acid, followed by crystallization and filtration to give the hydrochloride as solid.
In a preferred embodiment for preparing the compound of formula Ia or formula Ib, in step 4′) or step 4″), the deprotection can be carried out by the conventional methods in the field of organic chemistry to remove the hydroxy-protecting group, for example, by hydrogenolysis in the presence of catalyst to remove benzyl protective group, and cyclization is carried out in the presence of base; the catalyst used in the hydrogenolysis is Pd catalyst, such as Pd/C, Pd(OH)2, Pd(OAc)2, PdCl2, Pd; the base used in the cyclization is selected from alkali metal and alkaline earth metal hydroxide or carbonate, alkoxide, or organic heterocyclic base, such as NaOH, KOH, K2CO3, NaOMe, DBU; or the deprotection and the cyclization are carried out by hydrogenolysis using Pd/C as catalyst under basic condition to simultaneously remove benzyl protective group and perform cyclization, to directly give the cyclization product;
in step 5′) or step 5″), the sulfonyl halide used in the sulfonylation can be arylsulfonyl chloride or substituted arylsulfonyl chloride or alkylsulfonyl chloride, such as p-toluenesulfonyl chloride, phenylsulfonyl chloride, p-halophenylsulfonyl chloride, p-nitrophenylsulfonyl chloride, o-nitrophenylsulfonyl chloride or methylsulfonyl chloride; and the catalyst used in the reaction can be dialkyltin oxides, DMAP, such as dibutyltin oxide and 2,2-dibutyl-1,3,2-dioxastannolane; the base used in the reaction can be conventional organic base, such as pyridine, organic tertiary amine, such as triethylamine or diisopropylethylamine, the solvent in the reaction is organic aprotic solvent, such as methylene dichloride, chloroform, methyltetrahydrofuran, tetrahydrofuran, pyridine, toluene, ethyl acetate, acetonitrile, DMF, DMA, or a mixture of any two or more of them;
in step 6′) or step 6″), alkylation of amine is carried out by reaction of benzyl amine with corresponding sulfonate, the solvent in the reaction is organic aprotic solvent, such as methylene dichloride, chloroform, methyltetrahydrofuran, tetrahydrofuran, pyridine, toluene, ethyl acetate, acetonitrile, DMF, DMA, or a mixture of any two or more of them;
in step 7′) or step 7″), the base used in the cross-coupling reaction can be selected from inorganic base, such as K2CO3, Na2CO3, or organic tertiary amine, such as triethylamine or diisopropylethylamine, the solvent in the reaction is organic protic solvent, such as ethanol, propanol, isopropanol, or organic polar aprotic solvent, such as acetone, butanone, toluene, tetrahydrofuran, dimethylformamide, or a mixture of any two or more of these solvents;
in step 8′) or step 8″), the catalyst used in the deprotection reaction is Pd catalyst, such as Pd/C, Pd(OH)2, Pd(OAc)2, PdCl2, Pd, the solvent in the reaction is alcohol, ester or ether, or a mixture of any two or more of these solvents, such as methanol or ethanol.
In an embodiment, the step of converting the intermediate compound XIIIa or the intermediate compound XIIIb to the hydrochloride thereof is carried out by adding hydrochloric acid to the intermediate compound, such as 1N hydrochloric acid, followed by crystallization and filtration to give the hydrochloride as solid.
A skilled person in the art will understand that, in above process for preparation of the compound of formula Ia or formula Ib, the reaction product of any one of the above steps can be used as starting material to perform subsequent steps described above to prepare the compound of formula Ia or formula Ib. For example, the compounds of formula IXa and formula XIIa can be used as starting materials to perform steps 7′) to 8′) described above to obtain D-Nebivolol of formula Ia, or the compounds of formula IXb and formula XIIb can be used as starting materials to perform steps 7″) to 8″) described above to obtain L-Nebivolol of formula Ib.
In another aspect, the present invention also provides a mixture of D-Nebivolol (formula Ia) and L-Nebivolol (formula Ib) in any ratio,

wherein D-Nebivolol (formula Ia) and L-Nebivolol (formula Ib) are prepared according to the above processes, respectively.
In another aspect, the present invention also provides a process for preparation of a mixture of D-Nebivolol (formula Ia) and L-Nebivolol (formula Ib) in any ratio, the process comprising:
(1) according to the processes described in the above steps 3′) to 8′) and steps 3″) to 8″), preparing D-Nebivolol (formula Ia) and L-Nebivolol (formula Ib), respectively, and mixing them in any ratio; or
(2) according to the processes described in the above steps 3′) to 7′) and steps 3″) to 7″), preparing the hydrochloride of intermediate compound XIIIa and the hydrochloride of intermediate compound XIIIb, respectively, and mixing them in any ratio, neutralizing with base, and deprotecting the resulting mixture according to the method described in the step 8′); or
(3) according to the processes described in the above steps 3′) to 7′) and steps 3″) to 7″), preparing the hydrochloride of intermediate compound XIIIa and the hydrochloride of intermediate compound XIIIb, respectively, neutralizing them with base respectively to obtain free intermediate compound XIIIa and free intermediate compound XIIIb, mixing the two free intermediate compounds in any ratio, and deprotecting the resulting mixture according to the method described in the step 8′).
In another aspect, the present invention provides the compound of formula IV1′

wherein Ra is hydrogen or Ra is hydroxy-protecting group, which is selected from aralkyl, alkoxyalkyl, allyl or silyl protective group, such as t-BuMe2Si, t-BuPh2Si, (i-Pr)3Si, Et3Si, methoxymethyl, benzyl or —CH2Ar, wherein Ar is unsubstituted or substituted aryl, such as p-methoxyphenyl or halogen-substituted phenyl.
In another aspect, the present invention provides the compound of formula IV2′

wherein Rb is hydrogen or Rb is hydroxy-protecting group, which is selected from aralkyl, alkoxyalkyl, allyl or silyl protective group, such as t-BuMe2Si, t-BuPh2Si, (i-Pr)3Si, Et3Si, methoxymethyl, benzyl or —CH2Ar, wherein Ar is unsubstituted or substituted aryl, such as p-methoxyphenyl or halogen-substituted phenyl.
In another aspect, the present invention provides the compound of formula V′ (2R*,3R*)

wherein Rc is hydrogen or Rc is hydroxy-protecting group, which is selected from aralkyl, alkoxyalkyl, allyl or silyl protective group, such as t-BuMe2Si, t-BuPh2Si, (i-Pr)3Si, Et3Si, methoxymethyl, benzyl or —CH2Ar, wherein Ar is unsubstituted or substituted aryl, such as p-methoxyphenyl or halogen-substituted phenyl,
wherein the compound V′ is racemate, the relative configuration of which is represented by V′ (2R*,3R*), which is a recemic mixture consisting of equimolar amounts of Va′(2R,3R) and the enantiomer Vb′(2S,3S), such as the compounds having the following formulae wherein R is benzyl:

In another aspect, the present invention provides the compound of formula VI′ (2R*,3S*)

wherein Rd is hydrogen or Rd is hydroxy-protecting group, which is selected from aralkyl, alkoxyalkyl, allyl or silyl protective group, such as t-BuMe2Si, t-BuPh2Si, (i-Pr)3Si, Et3Si, methoxymethyl, benzyl or —CH2Ar, wherein Ar is unsubstituted or substituted aryl, such as p-methoxyphenyl or halogen-substituted phenyl,
wherein the compound VI′ is racemate, the relative configuration of which is represented by VI′ (2R*,3S*), which is a recemic mixture consisting of equimolar amounts of VIa′(2R,3S) and the enantiomer VIb′ (2S,3R), such as the compounds having the following formulae wherein Rd is benzyl:

In another aspect, the present invention provides the compound of formula XI′:

wherein R′ is substituted or unsubstituted aralkyl, C1-6 alkoxycarbonyl or C5-10 aralkoxycarbonyl, such as substituted or unsubstituted benzyl, tert-butyloxycarbonyl, benzyloxycarbonyl.
In another aspect, the present invention provides the compound of formula XII′:

wherein R′ is substituted or unsubstituted aralkyl, C1-6 alkoxycarbonyl or C5-10 aralkoxycarbonyl, such as substituted or unsubstituted benzyl, tert-butyloxycarbonyl, benzyloxycarbonyl.
In another aspect, the present invention provides the compound of formula XVI′:

wherein Re is hydrogen or Re is hydroxy-protecting group, said hydroxy-protecting group being selected from alkyl, haloalkyl, aralkyl, alkoxyalkyl, benzoyl, benzoyl in which the phenyl ring has substituent(s), or silyl protective group, such as t-BuMe2Si, t-BuPh2Si, (i-Pr)3Si, Et3Si, methoxymethyl, benzyl or —CH2Ar, wherein Ar is unsubstituted or substituted aryl, such as p-methoxyphenyl or halogen-substituted phenyl.
In an embodiment, the present invention also provides the following specific compounds for use in the synthesis of Nebivolol, selected from:    1-benzyloxy-2-bromomethyl-4-fluorobenzene,    4-[(2-benzyloxy-5-fluorophenyl)-butyn-1-yl]trimethylsilane,    1-(benzyloxy)-2-(butyn-3-yl)-4-fluorobenzene,    5-[2-(benzyloxy)-5-fluorophenyl]pent-2-yne-1-ol,    trans-5-[2-(benzyloxy)-5-fluorophenyl]pent-2-ene-1-ol,    (2R*,3R*)-3-[2-(benzyloxy)-5-fluorophenethyl]-2-hydroxymethyl-oxacyclopropane,    1-[6-fluoro-(2S*)-3,4-dihydro-2H-benzopyran-2-yl]-(1R*)-1,2-ethylene glycol,    cis-5-[2-(benzyloxy)-5-fluorophenyl]pent-2-ene-1-ol,    (2R*,3S*)-3-[2-(benzyloxy)-5-fluorophenethyl]-2-hydroxymethyl-oxacyclopropane,    1-[6-fluoro-(2R*)-3,4-dihydro-2H-benzopyran-2-yl]-(1R*)-1,2-ethylene glycol,    (S*,R*)-(+/−)-α-[(p-tolylsulfonyloxy)methyl]-(6-fluoro-2-chromanyl)-methanol,    (R*,R*)-(+/−)-α-[(p-tolylsulfonyloxy)methyl]-(6-fluoro-2-chromanyl)-methanol,    (S*,R*)-(+/−)-α-[(benzylamino)methyl]-(6-fluoro-2-chromanyl)-methanol,    (R*,R*)-(+/−)-α-[(benzylamino)methyl]-(6-fluoro-2-chromanyl)-methanol,    (2R,3R)-3-[2-(benzyloxy)-5-fluorophenethyl]-2-hydroxymethyl-oxacyclopropane,    (2S,3S)-3-[2-(benzyloxy)-5-fluorophenethyl]-2-hydroxymethyl-oxacyclopropane,    (2R,3S)-3-[2-(benzyloxy)-5-fluorophenethyl]-2-hydroxymethyl-oxacyclopropane,    (2S,3R)-3-[2-(benzyloxy)-5-fluorophenethyl]-2-hydroxymethyl-oxacyclopropane,    1-[6-fluoro-(2S)-3,4-dihydro-2H-benzopyran-2-yl]-(1R)-1,2-ethylene glycol,    1-[6-fluoro-(2R)-3,4-dihydro-2H-benzopyran-2-yl]-(1S)-1,2-ethylene glycol,    1-[6-fluoro-(2R)-3,4-dihydro-2H-benzopyran-2-yl]-(1R)-1,2-ethylene glycol,    1-[6-fluoro-(2S)-3,4-dihydro-2H-benzopyran-2-yl]-(1S)-1,2-ethylene glycol,    (S,R)-(+)-α-[(p-tolylsulfonyloxy)methyl]-(6-fluoro-2-chromanyl)-methanol,    (R,R)-(−)-α-[(p-tolylsulfonyloxy)methyl]-(6-fluoro-2-chromanyl)-methanol,    (R,S)-(−)-α-[(p-tolylsulfonyloxy)methyl]-(6-fluoro-2-chromanyl)-methanol,    (S,S)-(+)-α-[(p-tolylsulfonyloxy)methyl]-(6-fluoro-2-chromanyl)-methanol,    (S,R)-[(benzylamino)methyl]-(6-fluoro-2-chromanyl)-methanol, or    (R,S)-[(benzylamino)methyl]-(6-fluoro-2-chromanyl)-methanol.